CN113754619B - Method for preparing polysubstituted benzofuran-4-formic acid compound under catalysis of ruthenium - Google Patents
Method for preparing polysubstituted benzofuran-4-formic acid compound under catalysis of ruthenium Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis, and discloses a method for preparing a polysubstituted benzofuran-4-formic acid compound under the catalysis of ruthenium. Heating m-hydroxybenzoic acid compound, diaryl alkyne compound, ruthenium catalyst, additive and solvent in air or oxygen environment for reaction, separating and purifying reaction products to obtain polysubstituted benzofuran-4-formic acid compound. The high catalytic activity of the ruthenium catalyst system used in the method of the invention enables the reaction to use air or oxygen as a green oxidant, avoiding the use of toxic, dangerous or expensive oxidants. The reaction raw materials are easy to obtain, the solvent amount is small, the reaction is not sensitive to water, the operation is simple, convenient and safe, the reaction can be well amplified to gram-scale, and the industrialization is convenient to realize. The reaction of the invention is taken as a key step, the natural product dipterondsesin G with bioactivity can be conveniently synthesized, and the invention has good application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a polysubstituted benzofuran-4-formic acid compound under the catalysis of ruthenium.
Background
Polysubstituted benzofuran widely exists in natural products, bioactive molecules and drug molecules, and the efficient synthesis method has wide application prospects [ (a) Keylor M.H., matsuura B.S., stephenson C.R.J.chem.Rev.2015,115,8976; (b) Heravi m.m., zadsirjan v., hamdi h., amiri p.h.t.rsc adv.2017,7,24470; (c) Miao, y. -h.; hu, y. -h.; yang, j.; liu, t.; sun, j.; wang, x. -. J.rsc adv.2019,9,27510. Of these, 2,3-diarylbenzofurans are the core backbones of a large class of natural products with biological activity and are also key intermediates for the synthesis of these natural products and their analogs (Keylor m.h., matsuura b.s., stephenson c.r.j.chem.rev.2015,115, 8976). For example, dipterondonesin G can be used as an immunosuppressant, has activity against tumor cell proliferation, and can also selectively modulate estrogen receptor [ (a) Ge h.m., yang w.h., shen y., et al chem.eur.j.2010,16,6338; (b) Zhao z., wang l., james t., et al chem.biol.2015,22,1608; (c) Gao j., fan m., xiang g., et al, cell Death dis.2017,8, e2765. Recent research shows that dipterondonesin G has a remarkable effect of inhibiting proliferation of breast cancer cells and is expected to be a lead medicament for treating breast cancer (Fan M., chen J., gao J., et al. Cell Death Dis.2020,11,635). Many other natural products containing polysubstituted benzofuran skeletons, such as viniferifuran, malibotol A, shorea phenol, rhamneuronal C and the like, have good biological activity.
Based on the important biological activities of the above natural products and the prospects in drug development, their total synthesis and analogue synthesis are of great interest, with polysubstituted benzofuran-4-carboxylic acids and their derivatives being key intermediates for the synthesis of such natural products [ (a) Kim i, choi j.org.biomol.chem.2009,7,2788; (b) Kim k, kim i.org.lett.2010,12,5314; (c) Vo D.D., elofsson M.Adv.Synth.Catal.2016,358,4085; (d) Liu j. -t., do t.j., simmons c.j., et al, org.biomol.chem.2016,14,8927; (e) Singh d.k., kim i.j.org.chem.2018,83,1667 ]. However, the reported synthetic route needs to be subjected to multi-step reactions from complex raw materials, and is not highly universal, and a method for efficiently synthesizing the polysubstituted benzofuran-4-carboxylic acid from simple and easily available raw materials still needs to be further developed.
Alkyne cyclization of phenol is a highly efficient strategy for the synthesis of diarylbenzofurans. In 2013, sahoo et al reported that phenol and diaryl alkyne are activated by carbon-hydrogen bonds under palladium catalysis to obtain benzofuran (Kuram m.r., bhancandra m., sahoo a.k.angelw.chem.int.ed.2013, 52,4607). Thereafter, copper-catalyzed, rhodium-catalyzed, gold-catalyzed or zinc chloride-promoted reaction systems were developed gradually for the synthesis of benzofurans [ (a) Zhu r.y., wei j.b., shi z.j.chem.sci.2013,4,3706; (b) Zeng w., wu w.q., jiang h.f., et al.chem.commun.2013,49,6611; (c) Yeh c. -h., chen w. -c., grandepan p., et al, org.biomol.chem.2014,12,9105; (d) Liao j., guo p., chen q.cat.commun.2016, 77,22; (e) Sreenivasulu c, reddy a.g.k, satyanarayana g.org.chem.front.2017,4,972. However, no synthesis technology for constructing benzofuran rings by reaction of phenol compounds and alkynes catalyzed by ruthenium has been reported at present. Furthermore, none of the above synthetic techniques is suitable for the synthesis of carboxybenzofuran. In the reported reaction system, when hydroxybenzoic acid is used as a substrate to perform carbon-hydrogen bond activation and alkyne cyclization reactions, hydroxy isocoumarin or naphthol products are generated, and carboxybenzofuran compounds [ (a) Ueura k, satoh t, miura m.j.org.chem.2007,72,5362 cannot be obtained; (b) Ackermann l., postech j., graczyk., et al. (c) Hirosawa k., usuki y., satoh, t.adv.synth.cat.2019,361,5253; (d) Sihag P., juganmohan, M.J.org.chem.2019,84,2699.
Disclosure of Invention
Aiming at the defects and shortcomings of the prior art, the invention aims to provide a method for preparing a polysubstituted benzofuran-4-formic acid compound under the catalysis of ruthenium. The method takes m-hydroxybenzoic acid compounds as raw materials, the m-hydroxybenzoic acid compounds react with diaryl phenylacetylene under the catalysis of ruthenium, and polysubstituted 2,3-diaryl benzofuran-4-formic acid compounds are obtained through the alkenyl reaction and the oxidative cyclization reaction of carbon-hydrogen bonds connected in series. The method uses air or oxygen as an oxidant, and has the advantages of simple and easily obtained raw materials, convenient reaction operation and wide applicability. The method is taken as a key step, can conveniently synthesize the natural product dipterondsenin G with bioactivity, and has good application prospect.
The purpose of the invention is realized by the following technical scheme.
A method for preparing polysubstituted benzofuran-4-formic acid compounds under the catalysis of ruthenium comprises the following preparation steps: adding a m-hydroxybenzoic acid compound (I), diaryl alkyne (II), a ruthenium catalyst, an additive and a solvent into a reaction vessel, heating and stirring the mixture to react in an air or oxygen environment, and separating and purifying a reaction crude product to obtain polysubstituted benzofuran-4-formic acid products (III) and (IV), wherein the reaction formula is shown as a formula (1).
Wherein R is 1 、R 2 And R 3 Each independently selected from hydrogen and C 1 -C 8 Alkyl radical, C 6 -C 10 Aryl radical, C 1 -C 8 One of alkoxy, benzyloxy, halogen, trifluoromethyl, hydroxyl, carboxyl and ester group; ar (Ar) 1 And Ar 2 Relatively independently represent a substituted or unsubstituted aryl group; when Ar is 2 ＝Ar 1 When the reaction is carried out, the diaryl alkyne is symmetrical diaryl alkyne (V) to obtain a polysubstituted benzofuran-4-formic acid product (VI), and the reaction formula is shown as a formula (2);
preferably, the diaryl alkyne (II) has the following (VII) structure:
wherein R is 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 And R 13 Each independently selected from hydrogen and C 1 -C 8 Alkyl radical, C 6 -C 10 Aryl radical, C 1 -C 8 Alkoxy, benzyloxy, halogen, trifluoromethyl, trifluoromethoxy and ester group.
The ruthenium catalyst is at least one of a divalent ruthenium complex, a trivalent ruthenium complex, a divalent ruthenium salt and a trivalent ruthenium salt; preferably, the ruthenium catalyst is selected from one of p-cymene ruthenium dichloride dimer, phenyl ruthenium dichloride dimer, ruthenium trichloride hydrate, tris (triphenylphosphine) ruthenium dichloride and ruthenium acetate; more preferably, it is p-cymene ruthenium dichloride dimer.
The additive is an alkaline or chlorine-containing ionic additive; preferably, the additive is one of magnesium acetate tetrahydrate, anhydrous magnesium acetate, calcium acetate monohydrate, anhydrous calcium acetate, lithium acetate, sodium acetate, potassium acetate, guanidine carbonate and magnesium chloride; more preferably magnesium acetate tetrahydrate.
The solvent is a polar aprotic solvent; preferably, the solvent is a high boiling polar aprotic solvent, more preferably Gamma Valerolactone (GVL).
Preferably, the molar ratio of the diaryl alkyne (II) to the m-hydroxybenzoic acid compound (I) is 1 (0.8-2); more preferably 1.
Preferably, the molar amount of the catalyst is such that: the dosage of the contained metal ruthenium is 1 to 10 percent of the molar dosage of the diaryl alkyne (II); more preferably 3% to 5%.
Preferably, the molar amount of the additive is 10-60% of the molar amount of the diaryl alkyne (II); more preferably 15% to 30%.
Preferably, the amount of solvent is 0.5 to 5mL of solvent per 1mmol of diarylalkyne (II); more preferably, 1 to 1.5mL of solvent is used per 1mmol of diarylalkyne (II).
Preferably, the heating reaction refers to the reaction at 90-120 ℃ for 6-30 h; more preferably at 100 ℃ for 10 to 24h.
Preferably, the separation and purification means that the obtained reaction solution is cooled to room temperature, ethyl acetate is added for dilution, thin-layer diatomite is used for filtration, saturated sodium chloride or ammonium chloride solution and ethyl acetate are added for extraction, an organic phase is dried and concentrated, then silica gel column chromatography is used for separation, rotary evaporation is carried out, and drying is carried out, so as to obtain a purified product.
The principle of the invention is as follows: under the catalysis of ruthenium, carbon-hydrogen bond activation is carried out on the positions between carboxyl and hydroxyl in the m-hydroxybenzoic acid compound, and then the carbon-hydrogen bond activation and diaryl alkyne are subjected to addition reaction, and the generated alkenylation intermediate product is further subjected to oxidative cyclization reaction to obtain the polysubstituted benzofuran-4-formic acid compound. In the reaction, carboxyl is used as a guide group to assist ruthenium to carry out carbon-hydrogen bond activation, hydroxyl also assists a carbon-hydrogen bond functionalization process and participates in constructing furan rings, and the additive can promote the reaction.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The m-hydroxybenzoic acid compound and the diaryl alkyne used in the method are chemical raw materials with wide sources, the ruthenium catalyst can be directly purchased, and the ruthenium catalyst is relatively cheap in noble metal catalysts.
(2) The method uses air or oxygen as a green oxidant, avoids using toxic, dangerous or expensive oxidant, has only water as a byproduct, is convenient and safe to react, does not need special experimental equipment or water removal and oxygen removal operation, can be enlarged to gram-scale, and is convenient to realize industrialization.
(3) The reaction related to the method is compatible with various functional groups, the selectivity to most substrates is good, and the obtained product can be used for high-efficiency synthesis of a bioactive natural product dipterondionesin G and synthesis of other benzofuran natural products, and has good application prospects.
Drawings
FIG. 1 is a single crystal structural view of a product obtained in example 1.
FIG. 2 is a nuclear magnetic hydrogen spectrum of the product obtained in example 9.
FIG. 3 is a nuclear magnetic hydrogen spectrum of the product obtained in example 10.
FIG. 4 is a nuclear magnetic hydrogen spectrum of the product obtained in example 13.
FIG. 5 is a nuclear magnetic hydrogen spectrum of the product obtained in example 15.
FIG. 6 is a nuclear magnetic hydrogen spectrum of the product obtained in example 18.
FIG. 7 is a nuclear magnetic hydrogen spectrum of the product obtained in example 19.
FIG. 8 is a nuclear magnetic hydrogen spectrum of the product obtained in example 24.
FIG. 9 is a nuclear magnetic hydrogen spectrum of the product obtained in example 28.
FIG. 10 is a single crystal structural view of the product 3- (4-chlorophenyl) -2- (4-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid obtained in example 33.
FIG. 11 is a nuclear magnetic hydrogen spectrum of the product 3- (3,5-dimethoxyphenyl) -6-methoxy-2- (4-methoxyphenyl) -benzofuran-4-carboxylic acid obtained in example 34.
FIG. 12 is a nuclear magnetic hydrogen spectrum of the product dipterondsesin G obtained in example 35.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The reagents used in the examples are commercially available without specific reference.
Example 1
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The product 6-methyl-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (95.7 mg, 73% yield).
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum and carbon spectrum, high-resolution mass spectrum and single crystal X-ray diffraction analysis. 1 H NMR(600MHz,CDCl 3 )δ7.55–7.50(m,4H),7.38–7.36(m,2H),7.34–7.31(m,3H),7.25–7.22(m,3H),2.51(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ172.03,154.96,152.33,134.45,134.33,130.55,130.15,128.52,128.43,128.39,127.53,127.15,126.82,126.51,123.83,118.07,115.64,21.53；HRMS(ESI)calcd for C 22 H 16 O 3 [M-H] - 327.1027 and found 327.1027. The single crystal structure of the product is shown in fig. 1.
Example 2
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a holder, and the reaction tube was covered with the holder and attached to an oxygen balloon, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 6-methyl-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (93.5 mg, yield 71%).
Example 3
A10 mL reaction tube with a branch was charged with a magnetic stirrer, ruthenium trichloride hydrate (0.016mmol, 3.3mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), tolane (71.3mg, 0.4 mmol), anhydrous magnesium acetate (21.4 mg, 0.10mmol), and 0.5mL GVL in this order, and the upper port of the reaction tube was covered with a branch port open to the air, followed by stirring at 100 ℃ for 24 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (76.0 mg, yield 58%) which is the product 6-methyl-2,3-diphenyl benzofuran-4-formic acid.
Example 4
A magnetic stirrer, ruthenium acetate (0.016mmol, 4.5mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), tolane (71.3mg, 0.4 mmol), magnesium chloride (3.8mg, 0.04mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was covered with the upper port of the reaction tube and left open to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 6-methyl-2,3-diphenylbenzofuran-4-carboxylic acid was obtained by separating with a silica gel column chromatography using petroleum ether and ethyl acetate as eluents, rotary evaporating and draining to obtain a white solid (67.4 mg, yield 51%).
Example 5
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 5-hydroxy-2-methylbenzoic acid (73.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 5-methyl-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (106.7 mg, 81% yield).
Example 6
The starting material, 3-butyl-5-hydroxybenzoic acid (Sun h. -x., sun z. -h., wang b. Tetrahedron lett.2009,50,1596.) was first prepared using literature methods. A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-butyl-5-hydroxybenzoic acid (93.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (102.1 mg, yield 69%) which is the product 6-butyl-2,3-diphenyl benzofuran-4-formic acid.
Example 7
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-phenyl-5-hydroxybenzoic acid (102.8mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (110.4 mg, yield 71%) which is the product 2,3,6-triphenylbenzofuran-4-formic acid.
Example 8
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port of the reaction tube and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (107.5 mg, yield 78%) which is the product 6-methoxy-2,3-diphenyl benzofuran-4-formic acid.
Example 9
A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-4,5-dimethoxybenzoic acid (95.1mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL in this order, and the reaction tube was capped and left to communicate with the air at its branch, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (85.7 mg, yield 57%) which is the product 6,7-dimethoxy-2,3-diphenyl benzofuran-4-carboxylic acid.
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum analysis. 1 H NMR(600MHz,CDCl 3 )δ7.50–7.47(m,2H),7.4(s,1H),7.40–7.37(m,2H),7.35–7.33(m,1H),7.33–7.31(m,2H),7.25–7.26(m,3H),4.38(s,3H),4.0(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ170.65,152.73,147.59,146.05,138.09,134.39,130.36,130.16,128.61,128.47,128.39,127.53,127.07,126.10,118.19,116.40,112.55,61.25,57.35；HRMS(ESI)calcd for C 23 H 18 O 5 [M-H] - 373.1081 and found 373.1082. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 2.
Example 10
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-benzyloxy-5-hydroxybenzoic acid (117.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol), and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was covered with the upper port and left open to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 6-benzyloxy-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (110.8 mg, 66% yield).
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum analysis. 1 H NMR(600MHz,CDCl 3 )δ7.50–7.47(m,4H),7.44–7.41(m,3H),7.38–7.30(m,7H),7.26–7.23(m,3H),5.19(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ170.86,156.27,155.57,152.13,136.55,134.40,130.55,130.14,128.86,128.45,128.42,128.38,128.35,127.67,127.59,126.91,124.33,122.83,117.99,114.75,101.47,70.98；HRMS(ESI)calcd for C 28 H 20 O 4 [M-H] - 419.1289, found 419.1292. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 3.
Example 11
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-chloro-5-hydroxybenzoic acid (82.8mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 6-chloro-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (83.4 mg, yield 60%).
Example 12
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-bromo-5-hydroxybenzoic acid (104.2mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (95.1 mg, yield 61%) which is the product 6-bromo-2,3-diphenyl benzofuran-4-formic acid.
Example 13
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 2-fluoro-5-hydroxybenzoic acid (74.9mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (70.2 mg, yield 53%) which is the product 5-fluoro-2,3-diphenyl benzofuran-4-formic acid.
The structure of the obtained product is determined by a nuclear magnetic hydrogen spectrum, a carbon spectrum, a fluorine spectrum and a high-resolution mass spectrum. 1 H NMR(600MHz,DMSO-d 6 )δ13.17(brs,1H),7.82(dd,J＝8.9,3.7Hz,1H),7.49–7.44(m,5H),7.36–7.30(m,6H)； 13 C NMR(151MHz,DMSO-d 6 )δ164.17,154.91(d,J＝239.8Hz),152.73,149.41,131.29,130.00,129.29,129.18,128.71,128.70,128.23,126.55(d,J＝7.2Hz),117.67(d,J＝3.9Hz),115.28(d,J＝22.1Hz),113.39(d,J＝10.0Hz),112.76(d,J＝26.6Hz)； 19 F NMR(565MHz,DMSO-d 6 )δ-123.93；HRMS(ESI)calcd for C 21 H 13 O 3 F[M-H] - 331.0776, found 331.0777. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 4.
Example 14
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 2-chloro-5-hydroxybenzoic acid (82.8mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 5-chloro-2,3-diphenylbenzofuran-4-carboxylic acid was obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain a white solid (81.2 mg, 58% yield).
Example 15
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-trifluoromethyl-5-hydroxybenzoic acid (98.9mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (82.4 mg, yield 55%) which is the product 2,3-diphenyl-6-trifluoromethylbenzofuran-4-formic acid.
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum. 1 H NMR(600MHz,CD 3 OD)δ7.93(m,1H),7.74(m,1H),7.38–7.36(m,2H),7.32–7.30(m,3H),7.20–7.17(m,3H),7.15–7.13(m,2H)； 13 C NMR(151MHz,CD 3 OD)δ169.05,156.61,155.05,134.52,131.85,131.27,130.72,130.44,129.61,129.47,128.95,128.73,128.42,127.07(q,J＝33.2Hz),125.53(q,J＝271.1Hz),122.21(q,J＝3.8Hz),119.27,112.16(q,J＝3.9Hz)； 19 F NMR(565MHz,CD 3 OD)δ-62.73；HRMS(ESI)calcd for C 22 H 13 O 3 F 3 [M-H] - 381.0744, found 381.0743. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 5.
Example 16
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3,5-dihydroxybenzoic acid (74.0mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol), and 0.5mL of GVL were sequentially added to a 10mL reaction tube with a branch, and the reaction tube was covered with the upper port and left in communication with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (70.8 mg, yield 54%) which is the product 6-hydroxy-2,3-diphenyl benzofuran-4-formic acid.
Example 17
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3,5-dihydroxy-4-methylbenzoic acid (80.7mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was covered at the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (71.4 mg, yield 52%) which is the product 6-hydroxy-7-methyl-2,3-diphenyl benzofuran-4-formic acid.
Example 18
A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 4-bromo-3,5-dihydroxybenzoic acid (111.8mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL in this order, and the reaction tube was capped and left to communicate with the air at its branch, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (63.9 mg, yield 39%) which is the product of 7-bromo-6-hydroxy-2,3-diphenylbenzofuran-4-formic acid.
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum analysis. 1 H NMR(600MHz,CDCl 3 )δ7.45–7.46(m,2H),7.43–7.39(m,3H),7.32–7.30(m,2H),7.25–7.22(m,4H)； 13 C NMR(151MHz,CDCl 3 )δ169.87,154.25,153.47,152.83,135.26,131.43,131.24,129.51,129.47,129.36,128.69,127.70,126.71,122.11,119.89,114.60,96.15；HRMS(ESI)calcd for C 21 H 13 O 4 Br[M-H] - 406.9924 and found 406.9925. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 6.
Example 19
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 5-hydroxyisophthalic acid (87.4mg, 0.48mmol), tolane (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered with the upper port of the reaction tube and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as eluent, separating by silica gel column chromatography, rotary evaporating and pumping to obtain white solid (57.5 mg, yield 40%) which is the product 2,3-diphenyl benzofuran-4,6-dicarboxylic acid.
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum analysis. 1 H NMR(600MHz,CD 3 OD)δ8.32(d,J＝1.3Hz,1H),8.26(d,J＝1.3Hz,1H),7.50–7.48(m,2H),7.44–7.40(m,3H),7.31–7.29(m,3H),7.27–7.24(m,2H)； 13 C NMR(151MHz,CD 3 OD)δ169.81,168.89,156.68,155.29,134.78,132.57,131.27,130.93,130.35,129.58,129.45,128.85,128.43,127.86,127.71,126.93,119.54,116.15；HRMS(ESI)calcd for C 22 H 14 O 5 [M-H] - 357.0768 and found 357.0767. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 7.
Example 20
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-butylphenyl) acetylene (116.2mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was closed and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 2,3-bis (4-butylphenyl) -6-methylbenzofuran-4-carboxylic acid was obtained by separating with a silica gel column chromatography using petroleum ether and ethyl acetate as eluents, rotary evaporating and draining off the white solid (132.1 mg, yield 75%).
Example 21
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-methoxyphenyl) acetylene (95.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The product 2,3-bis (4-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid was obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporation and suction drying, and as a white solid (99.8 mg, yield 64%).
Example 22
The alkyne starting material, bis (4-benzyloxyphenyl) acetylene, was first prepared using literature procedures (Boger d.l., boyce c.w., labroli m.a., et al.j.am.chem.soc.1999,121, 54.). A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-benzyloxyphenyl) acetylene (156.2mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was closed and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to give a white solid (132.2 mg, yield 61%) which was the product 2,3-bis (4-benzyloxyphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 23
The alkyne starting material, di (2-methoxyphenyl) acetylene (Park k., bae g., moon j., et al.j.org.chem.2010,75,6244.) was first prepared using a literature method. A magnetic stirrer, p-cymene ruthenium dichloride dimer (0.02mmol, 12.2mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (2-methoxyphenyl) acetylene (95.3mg, 0.40mmol), guanidine carbonate (24.2mg, 0.20mmol) and 1mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was closed and the branch was allowed to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography on silica gel using petroleum ether and ethyl acetate as eluents, rotary evaporated and dried to give a white solid (69.5 mg, 45% yield) which was 2,3-bis (2-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 24
The alkyne starting material, di (2,4-methoxyphenyl) acetylene (Park k., bae g., moon j., et al, j. Org. Chem.2010,75,6244.) was first prepared using a literature method. A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (0.02mmol, 12.2mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (2,4-methoxyphenyl) acetylene (119.3mg, 0.40mmol), guanidine carbonate (24.2mg, 0.20mmol), and 1mL GVL in this order, and the reaction tube was closed at its upper port while leaving its branch open to the air, and then stirred at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (77.3 mg, yield 43%) which was 2,3-bis (2,4-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid.
The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum analysis. 1 H NMR(600MHz,CDCl 3 )δ7.55(s,1H),7.53(s,1H),7.23(dd,J＝8.5,2.0Hz,1H),7.08(d,J＝2.0Hz,1H),6.92–9.88(m,3H),6.79(d,J＝8.6Hz,1H),3.88(s,3H),3.87(s,3H),3.79(s,3H),3.66(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ171.70,154.67,152.30,149.34,149.10,148.57,148.50,133.94,127.31,126.77,126.55,123.55,123.32,122.76,119.96,116.33,115.35,113.65,111.43,110.99,109.99,56.07,56.05,55.94,55.63,21.51；HRMS(ESI)calcd for C 26 H 24 O 7 [M-H] - 447.1449 and found 447.1449. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 8.
Example 25
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-fluorophenyl) acetylene (85.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was covered with the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (102.3 mg, yield 70%) which was the product 2,3-bis (4-fluorophenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 26
A magnetic stirrer, p-cymene ruthenium dichloride dimer (0.01mmol, 6.1mg), 3-hydroxy-5-methylbenzoic acid (36.6 mg, 0.24mmol), bis (4-bromophenyl) acetylene (49.4 mg, 0.20mmol), guanidine carbonate (12.1mg, 0.10mmol), and 1mL of GVL were sequentially added to a 10mL reaction tube with a branch, and the reaction tube was capped and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated ammonium chloride solution was added, extracted with ethyl acetate and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (84.8 mg, yield 87%) which was the product 2,3-bis (4-bromophenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 27
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-trifluoromethylphenyl) acetylene (125.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube equipped with a branch, and the reaction tube was covered at the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (115.6 mg, yield 62%) which was the product 6-methyl-2,3-bis (4-trifluoromethylphenyl) benzofuran-4-carboxylic acid.
Example 28
First, the alkyne starting material bis (4-trifluoromethoxyphenyl) acetylene [ (a) Guo w., wu s., wang t., et al, org.chem.front.2018,5,1613; (b) Park k., bae g., moon j., et al.j. Org.chem.2010,75,6244. A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-trifluoromethoxyphenyl) acetylene (138.5mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was closed and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product 6-methyl-2,3-bis (4-trifluoromethoxyphenyl) benzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (108.7 mg, 55% yield).
The structure of the obtained product is determined by a nuclear magnetic hydrogen spectrum, a carbon spectrum, a fluorine spectrum and a high-resolution mass spectrum. 1 H NMR(600MHz,CDCl 3 )δ7.57(s,1H),7.50(s,1H),7.43–7.42(m,2H),7.27–7.25(m,2H),7.20–7.18(m,2H),7.05–7.04(m,2H),2.47(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ171.45,155.04,151.34,149.31(q,J＝1.6Hz),148.90(q,J＝1.7Hz),135.14,133.41,131.73,128.91,128.58,127.79,126.34,123.39,120.92,120.88,120.71(q,J＝257.1Hz),120.52(q,J＝257.8Hz),117.33,116.14,21.46； 19 F NMR(565MHz,CDCl 3 )δ-57.67,-57.75；HRMS(ESI)calcd for C 24 H 14 O 5 F 6 [M-H] - 495.0673, found 495.0672. The nuclear magnetic hydrogen spectrum of the product is shown in FIG. 9.
Example 29
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), 4,4' - (acetylene-1,2-diyl) dimethyl dibenzoate (117.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL were sequentially added to a 10mL reaction tube with a branch, the upper port of the reaction tube was covered and the branch was left open to the air, and then the reaction was stirred at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (103.5 mg, yield 58%) which was the product 2,3-bis (4-methoxycarbonylphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 30
The alkyne starting material, di (3,4-methoxyphenyl) acetylene (Lade d.m., pawar a.b., mainkar p.s., et al.j.org.chem.2017,82,4998.) was first prepared using literature methods. A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (3,4-dimethoxyphenyl) acetylene (119.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol), and 0.5mL GVL in this order, and the reaction tube was closed at the upper port while leaving the branch open to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (82.0 mg, yield 53%) which was 2,3-bis (3,4-dimethoxyphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 31
The alkyne starting material, di (3,5-methoxyphenyl) acetylene (Lade d.m., pawar a.b., mainkar p.s., et al.j.org.chem.2017,82,4998.) was first prepared using a literature method. A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (3,5-dimethoxyphenyl) acetylene (119.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL in this order, and the reaction tube was closed at the upper port and left at the branch port to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, followed by rotary evaporation and suction drying to obtain a white solid (123.9 mg, yield 69%) which was 2,3-bis (3,5-dimethoxyphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 32
The alkyne starting material, bis (4-methoxy-3,5-dimethylphenyl) acetylene (Park k., bae g., moon j., et al.j.org.chem.2010,75,6244.) was first prepared using a literature method. A10 mL reaction tube with a branch was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), bis (4-methoxy-3,5-dimethylphenyl) acetylene (117.8mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol), and 0.5mL GVL in this order, and the reaction tube was closed at the upper port and left open to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether and ethyl acetate were used as eluents, and silica gel column chromatography was used for separation, rotary evaporation and suction drying to obtain a white solid (99.7 mg, yield 56%) which was 2,3-bis (4-methoxy-3,5-dimethylphenyl) -6-methylbenzofuran-4-carboxylic acid.
Example 33
The alkyne starting material, 1-chloro-4- ((4-methoxyphenyl) ethynyl) benzene (Wu h., shao c., wu d., et al, j.org.chem.2021,86,5327.) was first prepared using literature methods. Then ruthenium catalytic reaction is carried out according to the following flow, and the reaction formula is shown as a formula (3).
A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), 1-chloro-4- ((4-methoxyphenyl) ethynyl) benzene (97.8mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, and the reaction tube was closed at the upper port and left to communicate with the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. And (2) taking petroleum ether and ethyl acetate as eluent, separating by using silica gel column chromatography, sequentially collecting solutions containing two isomers, respectively carrying out rotary evaporation and pumping to dryness to obtain two solid products.
The less polar, first-appearing product on the column was 3- (4-chlorophenyl) -2- (4-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid which, after rotary evaporation and suction drying, gave the product as a white solid (50.4 mg, 32% yield). The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum and carbon spectrum, high-resolution mass spectrum and single crystal X-ray diffraction analysis. 1 H NMR(600MHz,CDCl 3 )δ7.67–7.28(m,8H),6.85–6.84(m,2H),3.82(s,3H),2.56(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ171.45,160.01,154.86,152.84,134.10,133.60,133.28,131.78,128.70,128.62,127.19,126.65,123.06,122.93,115.76,115.35,114.07,55.42,21.51；HRMS(ESI)calcd for C 23 H 17 O 4 Cl[M-H] - 391.0743, found 391.0747. The single crystal structure of the product is shown in fig. 10.
The more polar, column-bound product was 2- (4-chlorophenyl) -3- (4-methoxyphenyl) -6-methylbenzofuran-4-carboxylic acid, which was rotary evaporated and dried to give the product as a white solid (73.4 mg, 47% yield). The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum. 1 H NMR(600MHz,CDCl 3 )δ7.56(s,1H),7.53(s,1H),7.47(d,J＝8.4Hz,2H),7.25–7.21(m,4H),6.93(d,J＝8.4Hz,2H),3.80(s,3H),2.54(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ171.02,159.26,154.92,151.25,134.64,134.40,131.18,129.15,128.75,128.24,126.88,126.67,126.28,123.90,118.12,115.59,114.14,55.36,21.57；HRMS(ESI)calcd for C 23 H 17 O 4 Cl[M-H] - 391.0743,found 391.0747。
Example 34 (Key intermediate for Synthesis of Natural product diptoindonesin G)
The alkyne starting material 1,3-dimethoxy-5- ((4-methoxyphenyl) ethynyl) benzene (Jeffrey j.l., sarpog r.tetrahedron lett.2009,50,1969.) was first prepared using literature methods, followed by a ruthenium-catalyzed reaction according to the following scheme. A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48mmol), 1,3-dimethoxy-5- ((4-methoxyphenyl) ethynyl) benzene (107.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL of GVL were sequentially placed in a 10mL reaction tube with a branch, the upper port of the reaction tube was closed and the branch was left open to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Separating with silica gel column chromatography using petroleum ether and ethyl acetate as eluent to obtain solution containing two isomers, and rotary steaming and drying to obtain crude product. The crude product is recrystallized by methanol, the mother liquor is separated by preparing a silica gel chromatographic plate by taking petroleum ether and ethyl acetate (1:1 mixed solution) as a developing agent, and two pure products are obtained.
3- (3,5-dimethoxyphenyl) -6-methoxy-2- (4-methoxyphenyl) -benzofuran-4-carboxylic acid precipitated during recrystallization and was less polar upon silica gel plate separation and dried to give the product as a white solid (64.7 mg, 37% yield). The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum. 1 H NMR(600MHz,CDCl 3 )δ7.53–7.50(m,2H),7.33(d,J＝2.3Hz,1H),7.26(m,1H),6.83–6.80(m,2H),6.51(d,J＝2.2Hz,2H),6.45(t,J＝2.2Hz,1H),3.93(s,3H),3.80(s,3H),3.71(s,6H)； 13 C NMR(151MHz,CDCl 3 )δ170.13,160.77,159.64,156.89,155.30,151.90,136.28,128.25,124.01,122.99,122.31,115.97,113.85,113.01,108.04,100.09,56.06,55.37,55.27；HRMS(ESI)calcd for C 25 H 22 O 7 [M-H] - 433.1293 and found 433.1292. The hydrogen spectrum of the product is shown in FIG. 11. The product can be converted into a natural product dipteronesin G with bioactivity through a two-step reaction by a method reported in the literature, and can also be used for synthesizing other benzofuran natural products and analogues thereof (Singh D.K., kim I.J.org.chem.2018,83,1667 vo D.D., elofsson M.adv.Synth.Cat.2016, 358,4085; kim I., choi J.org.Biomol.chem.2009,7,2788).
The mother liquor remained in the recrystallization and was more polar 2- (3,5-dimethoxyphenyl) -6-methoxy-3- (4-methoxyphenyl) -benzofuran-4-carboxylic acid upon silica gel plate separation to give the product as a white solid after drying (64.7 mg, 37% yield). The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum. 1 H NMR(600MHz,CDCl 3 )δ7.35(d,J＝2.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.27–7.25(m,2H),6.96–6.94(m,2H),6.73(d,J＝2.3Hz,2H),6.37(t,J＝2.3Hz,1H),3.94(s,3H),3.78(s,3H),3.63(s,6H)； 13 C NMR(151MHz,CDCl 3 )δ170.90,160.61,159.20,157.35,155.46,151.68,132.24,131.36,126.71,124.44,122.82,118.02,114.03,113.72,104.53,101.44,100.26,56.17,55.45,55.32；HRMS(ESI)calcd for C 25 H 22 O 7 [M-H] - 433.1293,found 433.1289。
Example 35 (Total Synthesis of Natural product dipterondesin G)
The method is used as a key step, can efficiently synthesize the natural product dipterondonesin G, and is carried out in three steps according to the following process, wherein the synthetic route is shown as a formula (4).
First, a benzofuran-4-carboxylic acid intermediate was synthesized with reference to example 33. A magnetic stirrer, p-cymene ruthenium dichloride dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48mmol), 1,3-dimethoxy-5- ((4-methoxyphenyl) ethynyl) benzene (107.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol), and 0.5mL GVL were sequentially added to a 10mL reaction tube having a branch port, and the reaction tube was covered with the upper port of the reaction tube and left in the branch port to the air, followed by stirring at 100 ℃ for 20 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and liquid separation was performed, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Separating with silica gel column chromatography using petroleum ether and ethyl acetate as eluent to obtain solution containing two isomers, and rotary steaming and drying to obtain crude product. The crude product was a mixture of two isomers, but was directly subjected to the next friedel-crafts reaction without further isolation. The crude product was dissolved in 5.0mL of anhydrous dichloromethane and trifluoroacetic anhydride (140. Mu.L, 1.0 mmol) was added. After stirring at room temperature for 12h, the reaction was quenched by addition of 20mL of methanol and the solvent and volatiles were removed by rotary evaporation. Petroleum ether and ethyl acetate were used as eluents, and the obtained product was separated by silica gel column chromatography to obtain a yellow solid (73.5 mg, 44% yield in two steps) which was the tetramethyl protected dipteroindonesin G.
Finally, demethylation reaction is carried out. The above yellow solid (62.5mg, 0.15mmol) was dissolved in 3mL of anhydrous dichloromethane, and a boron tribromide solution (3.0mL, 1.0mol/L dichloromethane solution) was added at-78 ℃. Then the system is allowed to self-warm to the room temperature, and after the reaction is continued for 16h, ice water is added to quench the reaction. Insoluble substances are filtered, washed by water and dichloromethane in sequence once, then dissolved in a small amount of acetone, added with petroleum ether, and precipitated precipitate is washed by petroleum ether once and is dried by pumping to obtain orange-red solid (47.1mg, 87 percent), namely the diptoindonesin G. The resulting product was structurally determined from nuclear magnetic hydrogen and carbon spectra, and the characterization data was consistent with literature dipterondionesin G isolated from plants (julianway l.d., sahidin, hakim e.h., et al. Nat. Prod. Commun.2009,4,947.). 1 H NMR(600MHz,acetone-d 6 )δ14.24(s,1H),7.81(d,J＝8.7Hz,1H),7.52(d,J＝1.7Hz,1H),7.32(d,J＝1.7Hz,1H),7.30(d,J＝2.3Hz,1H),7.08(d,J＝8.7Hz,1H),6.35(d,J＝2.2Hz,1H)； 13 C NMR(151MHz,acetone-d 6 ) δ 187.42,168.17,166.50,160.95,158.43,157.38,154.02,135.55,131.41,126.23,125.14,122.09,116.95,111.55,109.12,108.14,104.51,104.32,103.38. The hydrogen spectrum of the product is shown in FIG. 12.
Example 36 (gram-scale synthesis)
A25 mL reaction tube with a branched port was charged with a magnetic stirrer, p-cymene ruthenium dichloride dimer (45.9mg, 0.075mmol), 3-hydroxy-5-methoxybenzoic acid (1.009g, 6.0mmol), tolane (0.891g, 5.0mmol), magnesium acetate tetrahydrate (0.268g, 1.25mmol) and 4.0mL GVL in this order, and the reaction tube was covered with a port open to the air, followed by stirring at 100 ℃ for 24 hours. After the reaction, ethyl acetate was added, filtered through thin-layer celite, a saturated sodium chloride solution was added, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The product 6-methoxy-2,3-diphenylbenzofuran-4-carboxylic acid is obtained by separating with petroleum ether and ethyl acetate as eluents by silica gel column chromatography, rotary evaporating and draining to obtain white solid (1.261 g, 73% yield).
Comparative example 1
Reference is made to Pd-catalyzed benzofuran synthesis conditions in the literature (Kuram m.r., bhanuchandra m., sahoo a.k.angelw.chem.int.ed.2013, 52,4607). A10 mL Schlenk reaction tube was charged with a magnetic stirrer, tris (dibenzylideneacetone) dipalladium (9.2mg, 0.01mmol), 3-hydroxy-5-methylbenzoic acid (152.1mg, 1.0 mmol), tolane (35.6mg, 0.20mmol), sodium acetate (82.0mg, 1.0mmol), copper acetate monohydrate (40.0mg, 0.40mmol), and 2.0mL dioxane in this order. The reaction tube was sealed and the reaction was stirred at 130 ℃ for 48 hours. And adding ethyl acetate for dilution after the reaction is finished, wherein thin-layer chromatography analysis shows that a large amount of raw materials are remained and only trace products are generated, and gas chromatography-mass spectrometry analysis shows that the conversion rate of the tolane is less than 10%. Therefore, the Pd catalytic synthesis system is not suitable for synthesizing diaryl benzofuran-4-formic acid.
Comparative example 2
Reference is made to Cu-catalyzed benzofuran synthesis conditions in the literature (Zeng w., wu w.q., jiang h.f., et al.chem.commun.2013,49,6611). A10 mL Schlenk reaction tube was charged with a magnetic stirrer, copper trifluoromethanesulfonate (18.1mg, 0.05mmol), 3-hydroxy-5-methylbenzoic acid (114.1mg, 0.75mmol), tolane (89.1mg, 0.50mmol), zinc chloride (102.2mg, 0.75mmol), and 1.0mL nitrobenzene in that order. The reaction tube was charged with oxygen and connected with an oxygen balloon, and the reaction was stirred at 120 ℃ for 24 hours. After the reaction is finished, ethyl acetate is added for dilution, and thin layer chromatography analysis shows that a large amount of raw materials are remained and no product is generated. Therefore, the Cu catalytic synthesis system is not suitable for synthesizing diaryl benzofuran-4-formic acid.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (12)
1. A method for preparing polysubstituted benzofuran-4-formic acid compounds under the catalysis of ruthenium is characterized by comprising the following preparation steps:
adding a m-hydroxybenzoic acid compound (I), diaryl alkyne (II), a ruthenium catalyst, an additive and a solvent into a reaction vessel, heating and stirring the mixture to react in an air or oxygen environment, separating and purifying a reaction crude product to obtain products (III) and (IV) of the polysubstituted benzofuran-4-formic acid, wherein the reaction formula is shown as formula (1):
wherein R is 1 、R 2 And R 3 Each independently selected from hydrogen and C 1 -C 8 Alkyl radical, C 6 -C 10 Aryl radical, C 1 -C 8 One of alkoxy, benzyloxy, halogen, trifluoromethyl, hydroxyl, carboxyl and ester group; ar (Ar) 1 And Ar 2 Relatively independently represent a substituted or unsubstituted aryl group; when Ar is 2 ＝Ar 1 When the diaryl alkyne is a symmetric diaryl alkyne (V),obtaining a polysubstituted benzofuran-4-formic acid product (VI) with a reaction formula shown as a formula (2);
the ruthenium catalyst is at least one of a divalent ruthenium complex, a trivalent ruthenium complex, a divalent ruthenium salt and a trivalent ruthenium salt;
the additive is one of magnesium acetate tetrahydrate, anhydrous magnesium acetate, calcium acetate monohydrate, anhydrous calcium acetate, lithium acetate, sodium acetate, potassium acetate, guanidine carbonate and magnesium chloride;
the solvent is a polar aprotic solvent.
2. The method for preparing polysubstituted benzofuran-4-carboxylic acid compound according to claim 1, wherein said diaryl alkyne (II) has the following structure (VII):
wherein R is 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 And R 13 Each independently selected from hydrogen and C 1 -C 8 Alkyl radical, C 6 -C 10 Aryl radical, C 1 -C 8 Alkoxy, benzyloxy, halogen, trifluoromethyl, trifluoromethoxy and ester group.
3. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the ruthenium catalyst is one selected from p-cymene ruthenium dichloride dimer, phenyl ruthenium dichloride dimer, ruthenium trichloride, hydrated ruthenium trichloride, tris (triphenylphosphine) ruthenium dichloride and ruthenium acetate.
4. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 3, wherein: the ruthenium catalyst is p-cymene ruthenium dichloride dimer.
5. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the additive is magnesium acetate tetrahydrate.
6. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the solvent is gamma-valerolactone.
7. The method for preparing polysubstituted benzofuran-4-carboxylic acid compounds according to claim 1, which comprises the following steps: the molar ratio of the diaryl alkyne (II) to the m-hydroxybenzoic acid compound (I) is 1 (0.8-2).
8. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the molar usage of the catalyst is 1-10% of the molar usage of the diaryl alkyne (II) calculated by the usage of the contained metal ruthenium.
9. The method for preparing polysubstituted benzofuran-4-carboxylic acid compounds according to claim 1, which comprises the following steps: the molar dosage of the additive is 10-60% of the molar dosage of diaryl alkyne (II).
10. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the temperature of the heating and stirring reaction is 90-120 ℃, and the reaction time is 6-30 h.
11. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the amount of the solvent is 0.5-5 mL per 1mmol of diaryl alkyne (II); and the separation and purification means that the obtained reaction liquid is cooled to room temperature, ethyl acetate is added for dilution, the reaction liquid is filtered through thin-layer diatomite, saturated sodium chloride or ammonium chloride solution and ethyl acetate are added for extraction, an organic phase is dried and concentrated, then silica gel column chromatography is used for separation, and rotary evaporation and pumping drying are carried out, so that a purified product is obtained.
12. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 11, wherein: the amount of solvent is 1-1.5 mL solvent per 1mmol diaryl alkyne (II).
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